1. Field of the Invention
The present invention relates generally to the field of medicine and, more particularly, to prevention and treatment of diseases or conditions associated with elevated levels of endogenous sodium pump inhibitors, including, without limitation, the pregnancy-related conditions known as gestational hypertension, preeclampsia, eclampsia and intrauterine growth restriction.
2. Related Art
Conception results from the fertilization of an egg by a sperm and the development of the resulting embryo into a fetus. In order for pregnancy to be established and the embryo to develop it must embed itself within the uterine wall. At about 12 weeks' gestation a temporary disk-shaped organ forms (the placenta), enhancing the transfer of oxygen and nutrients to, and permitting the removal of waste products from, the fetus. The placenta is critical to fetal development, and improper placental formation is associated with preeclampsia and intrauterine growth restriction.
Upon conception, the fertilized egg (embryo) undergoes repeated cell division and cell migration to form a blastocyst, a single layer of cells surrounding a central cavity. One area of the blastocyst wall that is three or four cells thick, known as the embryonic pole, becomes recognizable as the embryo and eventually develops into the fetus. The remaining blastocyst cells form a structure called the trophoblast. Pregnancy begins upon implantation of the blastocyst. Implantation occurs when the trophoblasts proliferate and invade the uterine wall so that the blastocyst burrows into the central layer of tissue (endometrium). The trophoblasts then develop to form the chorion (outer membrane) and amnion (inner membrane) surrounding the embryo. The amniotic sac fills with fluid and expands to envelop the embryo. The embryo continues to grow but is confined within one wall of the uterus until about the 12th week of gestation. At that time, the endometrium tissue overlying the embryo comes in such close contact with the tissue of the opposite uterine wall that they fuse and obliterate the endometrial cavity. The only cavity that remains in the uterus is the amniotic cavity, containing amniotic fluid and the fetus.
Placentation begins at about 10 days' gestation, when the trophoblasts invade the endometrium and its blood vessels (spiral arterioles). As early as day 11 or 12, branch-like cell formations (villi) begin to form on the chorionic surface. Invasion of the maternal spiral arterioles causes maternal blood to leak into spaces between the villi, providing nourishment to the developing embryo. At about 12 weeks' gestation, the placenta begins to form as a distinct, disk-shaped organ. The placenta is attached by the villi to the decidua directly overlying maternal spiral arterioles. The maternal spiral arterioles empty maternal blood into the intervillous space so that the blood circulates around and through the latticework of villi. Nutrients are transferred from maternal blood in the intervillous space, across trophoblast cells, through the fibrous core of the villus, and through the endothelial cells of the fetal capillaries to the fetal blood. Fetal wastes move in the opposite direction. The placenta reaches its final development at approximately 18 to 20 weeks' of pregnancy.
It is generally known that abnormal placentation and placental vascular insufficiency are central features of certain pregnancy-related medical conditions, including, without limitation, preeclampsia and intrauterine growth restriction. Preeclampsia is a rapidly progressive condition, characterized by the occurrence of high blood pressure and abnormal levels of protein in the urine (proteinuria). Eclampsia is a more severe form of preeclampsia that is also characterized by seizures. Gestational hypertension is hypertension in pregnancy without proteinuria, and it may be a less severe form of or a precursor to preeclampsia. Preeclampsia and gestational hypertension may be further classified as mild or severe depending upon the severity of the clinical symptoms. These hypertension-related disorders are collectively referred to herein as “pregnancy-induced hypertension” or “PIH.”
Typically, clinical symptoms of PIH occur in the late second trimester or in the third trimester of pregnancy, although symptoms may occur earlier in pregnancy. PIH may be superimposed over other forms of hypertension, such as essential and secondary hypertension, that exist prior to or develop early in pregnancy. An increased risk for PIH is associated with first time pregnancies, when there is a large interval between pregnancies, pregnant women under the age of 20 or over the age of 35, women of black race, multi-gestational pregnancies, women who have conceived through in vitro fertilization (“IVF”), women who have had a prior pregnancy with PIH, women who have had a prior pregnancy conceived with a different partner, women with a family history of PIH or high blood pressure or diabetes, women who are of higher than normal weight or body mass index prior to pregnancy, undernutrition, women with a personal history of polycystic ovarian syndrome, insulin resistence or diabetes, hypertension, renal (kidney) disease, rheumatoid arthrisis, systemic lupus erythematosus or other autoimmune diseases, or thrombophilia risk factors. The risk of recurrent PIH in subsequent pregnancies is approximately thirty-three percent (33%), and PIH is superimposed in twenty-five percent (25%) of pregnancies in which chronic hypertension is present before pregnancy.
It is believed PIH occurs in five percent (5%) to ten percent (10%) of all human pregnancies. PIH disorders are a leading global cause of maternal and infant illness and death. PIH occurs in over six million births a year and is responsible for 15 percent of all premature births. By conservative estimates, these disorders are responsible for 76,000 deaths each year. The risk of death for a pregnant woman with severe preeclampsia is 0.5%, and the risk of perinatal death for her baby is 13%; if the condition remains untreated and eclampsia develops, the risk of maternal and fetal death increases to 5% and 28%, respectively. Zupan J., Perinatal Mortality in Developing Countries, New Engl J. Med. 352(20) 2047-248 (2005).
PIH is a syndrome having maternal and fetal manifestations. The maternal condition is characterized by vasospasm, activation of the coagulation system, oxidative stress and inflammatory-like responses, all of which have detrimental effects on the placenta, kidney, blood, liver, vasculature, cardiopulmonary system and brain. PIH is a systemic syndrome, and several of its non-hypertensive symptoms and complications may be life-threatening even with only mild increases in blood pressure.
Intrauterine growth restriction or retardation (“IUGR”) and intrauterine fetal demise are fetal symptoms of or complications associated with PIH. IUGR is the second leading cause of perinatal morbidity and mortality, and it occurs in approximately 5% of the general obstetric population. Placental insufficiency, preeclampsia and abnormal placentation are generally recognized by those skilled in the art as being among the causes of or contributory factors in IUGR.
Women who develop mild gestational hypertension after 37 weeks' gestation have pregnancy outcomes similar to those of pregnant women who are normotensive, apart from increased rates of induced labor and cesarean delivery. Conversely, women with severe gestational hypertension have high rates of placental abruption, preterm delivery and small-for-gestational-age babies (the postnatal counterpart and likely result of IUGR) similar to those of women with severe preeclampsia. Twenty-five percent (25%) of cases of eclampsia occur postpartum, usually in the first 2 to 4 days after delivery.
After a diagnosis of severe PIH, the baby is generally induced and delivered if it is near term, i.e., after 36 weeks. However, if PIH occurs earlier in the pregnancy, its impact is more profound because fetal viability is low; infant death occurs in approximately 87% of these cases. For pregnancies in which PIH occurs earlier than 24 weeks, the induction of labor is recommended and results in essentially 100% neonatal mortality. For pregnancies between 24 and 28 weeks' gestation, management of PIH may be attempted to increase gestational age, provided that there is close monitoring for maternal and fetal complications. Regardless of gestational age of the fetus, delivery is the management method of choice for eclampsia.
To date, there is no cure or effective treatment for PIH or IUGR. Delivery of the baby and placenta usually resolves the maternal symptoms of PIH within twelve (12) weeks' postpartum. However, if the baby is not near term then early delivery is generally contrary to the best interests of the baby. Prophylactic measures against PIH, including calcium supplementation, vitamin and antioxidant supplementation and aspirin therapy, have not proven to be successful.
Depending upon the stage of the pregnancy and the severity of maternal and fetal conditions, gestational hypertension, preeclampsia, eclampsia, and IUGR may be managed in an attempt to prolong the pregnancy and advance the gestational age to improve the fetal outcome. If maternal symptoms persist after delivery, management of PIH symptoms is necessary to prevent deterioration of the maternal condition or further development of complications.
Traditional management of PIH includes bed rest and antihypertensive and/or anticonvulsant therapy, including, without limitation, hydralazine, nifedipine, sodium nitroprusside, 1-methyldopa (e.g., Aldomet®), atenolol, labetalol, magnesium sulfate and phenytoin. Management of IUGR includes treatment of the concomitant maternal disease (e.g., gestational hypertension or preeclampsia) and bed rest. Preterm delivery may be necessary to prevent intrauterine demise due to chronic fetal oxygen deprivation or if the maternal condition does not respond to management efforts.
The cause(s) of PIH and IUGR remain elusive. The extensive list of possible causes currently being investigated by those skilled in the art include (1) immunologic factors (maternal reaction to paternal antigen or circulating auto-antibodies that activate angiotensin II), (2) genetic factors, (3) insulin resistance and increased levels of insulin, free fatty acids and triglycerides, (4) dietary calcium deficiency, (5) increased oxidative stress, (6) prostaglandin imbalance (increased ratio of thromboxane to prostacyclin), and (7) circulating pro-angiogenic factors and their inhibitors (e.g., soluble fms-like tyrosine kinase 1, an agonist of vascular endothelial growth factor and placental growth factor). Roberts J M and Gammill H S, Preeclampsia Recent Insights, Hypertension (December 2005) 1243-1249; Noris M, et al., Mechanisms of Disease: Preeclampsia, Nature of Clinical Practice Nephrology 1(2): 98-110 (December 2005); Solomon C G and Seely E W, Preeclampsia—Searching for the Cause, N. Engl. J. Med. 350(7):641-642 (2004); Davison, J M, et al., New Aspects in the Pathophysiology of Preeclampsia, J. Am. Soc. Nephrol. 15:2440-48 (2004); Pridjian G and Puschett J B, Preeclampsia Part 2: Experimental and Genetic Considerations, Obstet. Gynecol. Survey 57(9):619-634 (2002)(summarizing early research to determine the role of endogenous digitalis-like factors in preeclampsia and concluding that results are unclear).
Notwithstanding the state of the art and various popular theories being investigated by others in the field, it is theorized by Applicant that certain endogenous “digoxin-like” factors originating from maternal, placental and/or fetal sources may be a cause of or a contributing factor in these conditions. Serum of adult patients in renal or liver failure, pregnant women, neonates and umbilical cord blood evidence endogenous factors that cross-react with anti-digoxin antibodies when assayed with commercially available immunoassays for digoxin. Some, but not all, studies have shown that these endogenous factors are present at higher levels in women with preeclampsia than in women without preeclampsia.
These endogenous factors have generally been referred to as endogenous “digoxin-like,” “digitalis-like,” “endoxin,” “endobain,” “sodium pump inhibitors” or “sodium pump ligands” not only because they cross-react with digoxin antibodies, but because they are also known to inhibit activity of sodium/potassium ATPase in vitro. Certain known exogenous sodium pump inhibitors belong to classes of compounds known as cardenolides and bufadienolides, commonly referred to as cardiotonic steroids or cardiac glycosides. The aglycone moieties of cardenolides and bufadienolides are also known to be sodium pump inhibitors. Pullen M A, et al., Characterization of the Neutralizing Activity of Digoxin-Specific Fab Toward Ouabain-like Steroids, J. Pharm. and Exp. Therapeutics 310(10): 319-325 (2004).
For the better part of a generation, the possible role of these endogenous factors in PIH and IUGR has been generally discounted or discredited by leading investigators in the field, who found that there was no difference between levels of endogenous factors in women with and without preeclampsia and who, therefore, concluded that endogenous factors are not predictive of and do not play a major role in preeclampsia. See, Gonzales, A R, et al., Digoxin-like Immunoreactive Substance in Pregnancy, Am. J. Obstet. Gynecol. 157(3):660-664 (1987); Phelps, S J, et al., The Influence of Gestational Age and Preeclampsia on the Presence and Magnitude of Serum Endogenous Digoxin-like Immunoreactive Substance(s), Am. J. Obstet. Gynecol. 158(1): 34-39 (1988). Thus, endogenous factors are not among the models of PRI or IUGR being currently suggested or investigated by other researchers generally skilled in the art. Roberts J M and Gammill H S, Hypertension (December 2005) 1243-1249; Noris M, et al., Nature of Clinical Practice Nephrology 1(2): 98-110 (December 2005); Solomon C G and Seely E W, N. Engl. J. Med. 350(7):641-642 (2004); Davison, J M, et al., J. Am. Soc. Nephrol. 15:2240-48 (2004); Redman C W, Sargent I L, Latest Advances in Understanding Preeclampsia, Science 308(5728):1592-94 (2005); Pridjian G and Puschett J B, Obstet. Gynecol. Survey 57(9):619-634 (2002).
Applicant has discovered that symptoms of PIH and IUGR may be due, in whole or in part, to inhibition of the sodium pump by endogenous factors. It is theorized by Applicant that a decrease in sodium pump activity, particularly in vascular endothelial cells, may cause an increase in intracellular sodium and calcium ions, promoting vasoconstriction, vasospasm and the resultant hypertension found in PIH. Furthermore, in placental cells, many nutrient transport processes are coupled to Na+ transport and energized by the Na+ gradient. Thus, Applicant believes that inhibition of the sodium pump by these endogenous factors may also impair nutrient and oxygen supply to the placenta, restrict nutrient and blood flow to the developing fetus, and limit the removal of metabolic waste products from the fetus—all of which cause or contribute to IUGR.
It is known that, in vitro, sodium pump inhibition by endogenous factors may be reversed or prevented by addition of antibodies to cardenolides and bufadienolides, particularly digoxin immune Fab. Pullen M A, et al., J. of Pharm. and Exp. Therapeutics 310(10): 319-325 (2004). As disclosed in the prior and co-pending U.S. application Ser. Nos. 10/202,957, 10/292,338, and 60/681,693, Applicant has discovered that antibodies to cardenolides and bufadienolides are useful in diagnosing and/or treating the causes, symptoms and/or complications of PIH and IUGR.
Determination of an effective antibody composition requires, inter alia, a determination of the body load of antigen that must be neutralized by the antibody. There is no known available immunoassay specific for the endogenous factors that Applicant believes cause or contribute to PIH and IUGR. However, commercially available immunoassays have been developed to detect digoxin, ouabain and marinobufagenin. Commercially available immunoassays for exogenous cardiac glycosides (particularly, immunoassays for digoxin, oubain and marinobufagenin) that have been used to detect serum levels of endogenous factors in pregnant women with and without preeclampsia, have detected the following levels of endogenous factors: <0.1 to 1.5 ng/mL, “digoxin”; 0.54 to 0.86 nmol/L, “ouabain”; and 2.53 to 2.73 nmol/L “marinobufagenin.” Lopatin D A, et al., Circulating Bufodienolide and Cardenolide Sodium Pump Inhibitors in Preeclampsia, J. Hypertension 17(8): 1179-1187 (1999); Adair C D, et al., Elevated Endoxin-Like Factor Complicating a Multifetal Second Trimester Pregnancy: Treatment with Digoxin-Binding Immunoglobulin, Am. J. Nephrol. 16:529-531 (1996); Seely E W, et al., Markers of Sodium and Volume Homeostasis in Pregnancy-Induced Hypertension, J. Clin. Endocrinol. Metabol. 74(1): 150-156 (1992); Craig H R, et al., Binding of Endogenous Digoxin-like Immunoreactive Factor to Serum Proteins During Normal and Hypertensive Pregnancy, J. Clin. Immunoassay 14(4): 245-250 (1991); Goodlin R C, Antidigoxin Antibodies in Eclampsia, N. Engl. J. Med. 618(8): 518-519 (Feb. 25, 1988); Goodlin R C, Will Treatment with Digoxin Antibody Benefit Pregnant Patients with Toxemia and Elevated Digoxin Like Factor?, Medical Hypothesis 24:107-110 (1987); Beyers A D, et al., The Possible Role of Endogenous Digitalis-like substance in the Causation of Pre-eclampsia, SA Medical Journal, 65: 883-885 (1984); Gusdon J P, et al., A Digoxin-like Immunoreactive Substance in Preeclampsia, Am. J. Obstet. & Gynecol. 150:83 (1984); Graves S W and Williams G H, An Endogenous Ouabain-like Factor Associated with Hypertensive Pregnant Women, J. Endocrinol. Metab. 59:1070 (1984).
However, it is also known that there is variation among immunoassays in detecting endogenous “digoxin-like” factors. Furthermore, a number of substances such as steroids, lipids and bile are known to cross-react with anti-digoxin antibodies and may interfere with detection of endogenous factors in patients who have not been treated with digoxin or digitalis. Ghione S, et al., Endogenous Digitalis-like Activity in the Newborn, J. Cardio. Pharmacol. 22: S25-S28 (1993); McMillan G A, et al., Comparable Effects of Digibind and DigiFab in Thirteen Digoxin Immunoassays, Clin. Chemistry 48(9): 1580-84 (2002); Pudek M R, et al., Seven Different Digoxin Immunoassay Kits Compared with Respect to Interference by a Digoxin-Like Immunoreactive Substance in Serum from Premature and Full Term Infants, Clin. Chem. 29(11): 1972-1974 (1983).
Thus, Applicant believes that immunoassays specific for exogenous cardenolides or bufadienolides, including digoxin immunoassays, have not accurately detected the levels of endogenous factors in pregnant patients. It is believed that a substantial portion of endogenous factors, perhaps up to 90%, are protein-bound and not detectable by direct measurement with conventional immunoassay techniques. Valdes R, Graves S W, Protein binding of Endogenous Digoxin-immunoactive Factors in Human Serum and its Variation with Clinical Condition, J. Clin. Endocrinol. Metabol. 60:1135-1143 (1985). This is further evidenced because sodium pump inhibition by endogenous factors substantially exceeds that which would be expected based upon the levels of endogenous factors detected by conventional immunoassay. Pullen M A, et al., J. of Pharm. and Exp. Therapeutics 310(10): 319-325 (2004).
The discrepancy in immunoassay measurements of endogenous factors and lack of concordance with sodium pump inhibition suggests that there are differences between endogenous factors and exogenous cardenolides and bufadienolides. Miyagi H, et al., Ouabain-like Na/K-ATPase Inhibitory Activity of a Plasma Extract in Normal Pregnancy and Pregnancy Induced Hypertension, Japan. J. Pharmacol. 57: 571-581 (1991). Thus, it is theorized by Applicant that the endogenous factors are not digoxin, ouabain, bufalin, marinobufagenin or other known exogenous cardenolides and bufadienolides, but are one or more compounds that differ in biological, chemical, physical, biopharmaceutical and/or pharmacokinetic characteristics from exogenous cardiac glycosides.
Applicant has discovered that if antibodies to exogenous cardenolides and bufadienolides are to be useful in diagnosing, preventing and/or treating PIH and IUGR, an effective antibody composition may not be determined solely upon measurements of endogenous factors resulting from immunoassays specific for exogenous cardiac glycosides, such as digoxin, ouabain, bufalin or marinobufagenin.
Except as described in related U.S. application Ser. Nos. 10/202,957, 10/292,338, and PCT/US2003/023235, WO 2004/011028 A1 (each of which applications is incorporated herein by this reference), there is no known efficacious composition of antibodies that bind digoxin (including any other exogenous cardenolide or bufadienolide that is not specific for digoxin), or method of using such antibody compositions, for predicting, preventing, diagnosing or treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction.
Goodlin (1988) and Adair, et al. (1996) have investigated the effects of digoxin antibodies on preeclampsia in vivo. These investigators administered antibody compositions based upon measured serum digoxin concentrations, doses and standard dosing formulas for treating digoxin intoxication. These initial experiments failed to establish digoxin antibody compositions that were effective for treating the symptoms of preeclampsia, extending pregnancy or advancing fetal development.
In the first experiment, Goodlin intravenously administered 10 mg total digoxin antibodies to a preeclamptic patient having a serum endogenous factor level of 0.3 ng/mL (as determined by digoxin immunoassay). The 10 mg composition was repeated once after 12 hours. Each antibody composition administered to the patient produced a precipitous, albeit transient, reduction in mean blood pressure. The patient's blood pressure began to rise approximately one hour after each antibody composition was administered. Goodlin did not report the reduction in mean blood pressure to be statistically significant. Furthermore, the results cannot be attributed solely to administration of digoxin antibodies because of the concurrent intravenous administration of antihypertensive drugs and albumin. Goodlin states that the increase in urinary output was due, in part, to concurrent administration of albumin. However, Goodlin did not address the synergistic or combined effects of the antihypertensive drug administration in combination with digoxin antibodies. Regrettably, and most significantly from a scientific and medical perspective, the pregnancy was terminated prematurely and the fetus did not survive. Goodlin R C, New Engl. J. Med. 618(8): 518-519 (1988).
In the second experiment, Adair, et al., administered a single composition of 29 mg total digoxin antibodies to a patient (twin gestation) exhibiting a serum endogenous factor level of 0.4 ng/mL (as determined by digoxin immunoassay). The composition was given as a partial bolus (5 mg) and a slow infusion at a rate of 1 mg/hour for 24 hours. Although mean arterial pressure gradually declined until approximately 12 hours after the treatment commenced, the reduction was not statistically significant. Moreover, during digoxin antibody treatment the patient exhibited more than a two-fold increase in proteinuria. The worsening proteinuria led to premature termination of the pregnancy and, as in Goodlin, neither of the fetuses survived. Adair C D, et al., Am. J. Nephrology 16:529-531 (1996). Thus, neither Goodlin nor Adair established an antibody composition that was therapeutically effective for treating preeclampsia.
Endogenous factors may also cross-react with antibodies specific for other non-digoxin cardenolides or bufadienolides, such as bufalin, ouabain or marinobufagenin. PCT US 2004/002802, WO 2004/071273 A2 (republished WO 2004/071273 A3) (incorporated herein by this reference), claims that increasing urinary levels of marinobufagenin are a diagnostic indicator of preeclampsia. This patent application has also generally suggested that antibodies to marinobufagenin may be used to treat preeclampsia. However, patent application WO 2004/071723 does not teach a therapeutically effective composition or dosing administration regimen for treating preeclampsia with marinobufagenin antibody.
To date, PIH is believed to be a condition specific to humans. Thus, there is no known naturally occurring animal model of PIH available for the study of gestational hypertension, preeclampsia or eclampsia. Recently, some investigators have attempted to create an animal model by administering a high salt diet to pregnant rats and suggesting that pregnant rats on the high salt (NaCl) diet exhibit symptoms of “preeclampsia.” It has been shown that an antibody to marinobufagenin lowers blood pressure in the pregnant rats on high NaCl intake. Fedorova et al., Antibody to Marinobufagenin Lowers Blood Pressure in Pregnant Rats on a High NaCl Intake, J. Hypertension 2005: 23(4):835-842. However, this proposed animal model has substantial differences from naturally occurring preeclampsia in humans. For example, the manner of trophoblast invasion and placentation are significantly different between rats and humans. The mild increase in urinary protein in the rats does not approach significant proteinuria (>300 mg/24 hours) that evidences preeclampsia in humans. Furthermore, the results of the antibody “treatment” are suspect because the treatment was with whole antibody and not Fab fragments. Therefore, the resulting reduction in blood pressure in rats may be due, in whole or in part, to an allergic or immune reaction to whole antibody instead of a “binding-inactivation” of the endogenous factor by the antibody. Another major difficulty in designing or evaluating a study involving an animal model of preeclampsia relates to the manipulation and intervention to which the animal is subjected. This includes a number of factors such as the handling of the animals, the route of administration of any agent, and the methods used to measure the different variables, particularly blood pressure. Most methods for measuring blood pressure require restraining or tethering the animal which could lead to artificial elevation of blood pressure, especially in cases where compensatory mechanisms have been eliminated. The effect of stress in the animals caused by the required manipulation, in and of itself, has been clearly shown to result in changes which could mimic preeclampsia. Thus, this recently proposed animal model has not proven to be an accurate model of true preeclampsia and has not been generally accepted for the study of preeclampsia.
Applicant has disclosed in related U.S. application Ser. No. 10/202,957 that administering anti-digoxin antibodies to preeclamptic women mitigates or reverses the symptoms or complications of PIH and IUGR. It is believed that by mitigating or reversing the symptoms or complications of PIH, PIH and IUGR will be controlled, the pregnancy may be extended and fetal development may be advanced. Also, in related U.S. application Ser. No. 10/292,338 and PCT/US2003/023235, WO 2004/011028 A1 it has been further disclosed that antibodies to digoxin may be used to control or regulate, inter alia, Na+/K+ ATPase, to improve maternal blood flow, nutrient exchange and metabolic waste removal between the maternal vasculature and the placenta and fetus, and to prevent or limit IUGR.
The present invention is directed to overcoming one or more of the problems set forth above, including overcoming the lack of a pharmaceutical composition that is effective for preventing or treating one or more causes, symptoms or complications of PIH or IUGR, that does not have adverse side effects, and that prolongs a PIH or IUGR pregnancy to allow further development of the fetus. It would be particularly beneficial for pregnancy to be prolonged for a period of time sufficient to administer therapeutically effective doses of corticosteroids or other pharmaceutical compositions that either advance fetal organ development or that prevent or limit the adverse physical consequences in the neonate that may be due, in whole or in part, to premature delivery. It would also be beneficial to have a pharmaceutical composition that is effective for treating one or more causes, symptoms or complications of PIH that occur or persist after delivery of the fetus, and particularly for treating symptoms or complications of PIH that are not managed by or responsive to traditional antihypertensive drugs or anti-convulsant or other agents used to manage seizures, HELLP, ocular or neurological deficits or disturbances, or any other symptom or complication of PIH that develops or continues postpartum.
Because the specific etiologies of gestational hypertension, preeclampsia, eclampsia and intrauterine growth restriction remain elusive, the medical definitions or diagnostic indicators of these conditions continue to be revised from time to time. Thus, any conventional diagnostic or prognostic method for assessment of the risk of or determining the presence of chronic or essential hypertension, gestational hypertension, preeclampsia, eclampsia or IUGR may be used in connection with the invention. The inventions described herein are not limited in any manner by the descriptions, definitions, diagnostic or clinical indications of PIH or IUGR described herein, and are deemed to include all existing and future revisions to the medical definitions or diagnostic or prognostic indicators of gestational hypertension, preeclampsia, eclampsia, any other form of hypertension exhibited during pregnancy, and intrauterine growth restriction.